Parkinson's disease (PD) is a chronic neurodegenerative disorder. Although we do not yet understand its cause, there is extensive degeneration of nigro-striatal DA neurons. Powerful neurotrophic factors which could be used for the treatment of PD, like GDNF, have been described recently. The ultimate goal of this proposal is to develop novel high-capacity adenoviral systems for cell-type specific, inducible, long term, stable, and non-immunogenic delivery of neuroprotective genes to the brain for both experimental transgene expression in adult animals, and for the future treatment of chronic neurodegenerative diseases such as PD and Alzheimer's disease by gene therapy. Currently the use of adenovirus vectors has been limited by the low efficiency of transcriptional promoter elements currently used, which directly leads to the need to use higher doses of vectors, and the cytotoxicity and immunogenicity of viral proteins expressed from the genornes of first generation adenoviral vectors. We now wish to develop novel cell-type specific and inducible vectors, that will allow efficient, safe, and long-term gene delivery vectors for neurological gene therapy. We will construct high-capacity helper-dependent adenoviral vectors that express no adenoviral genes. We will utilize the powerful, astrocyte specific major immediate early murine Cytomegalovirus promoter, driving novel tetracycline-dependent transcriptional activators to achieve cell-type specific and regulatable expression of GDNF. The efficacy, cell-type specificity, and inducibility of these vectors will be tested stringently to assess their capacity to deliver cell-type specific and regulatable GDNF, and also to determine any potential side effects caused either by the vectors or the long term expression of powerful neurotrophic agents. The reagents and principles established by this work will be of substantial value to those with interests in the basic and clinical neurosciences, and will lead to the development of novel, efficient, and safe approaches for the treatment of human chronic neurodegenerative diseases. This research will facilitate the development of the tools needed to achieve long-lived, safe, cell-type specific, regulatable, non-cytotoxic transgene expression, and, ultimately, for the treatment of patients suffering from chronic neurodegenerative diseases.